Human MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases

Hum Mol Genet. 1997 Jul;6(7):1117-23. doi: 10.1093/hmg/6.7.1117.


The expansion of trinucleotide repeat sequences is associated with several neurodegenerative diseases. The mechanism of this expansion is unknown but may involve slipped-strand structures where adjacent rather than perfect complementary sequences of a trinucleotide repeat become paired. Here, we have studied the interaction of the human mismatch repair protein MSH2 with slipped-strand structures formed from a triplet repeat sequence in order to address the possible role of MSH2 in trinucleotide expansion. Genomic clones of the myotonic dystrophy locus containing disease-relevant lengths of (CTG)n x (CAG)n triplet repeats were examined. We have constructed two types of slipped-strand structures by annealing complementary strands of DNA containing: (i) equal numbers of trinucleotide repeats (homoduplex slipped structures or S-DNA) or (ii) different numbers of repeats (heteroduplex slipped intermediates or SI-DNA). SI-DNAs having an excess of either CTG or CAG repeats were structurally distinct and could be separated electrophoretically and studied individually. Using a band-shift assay, the MSH2 was shown to bind to both S-DNA and SI-DNA in a structure-specific manner. The affinity of MSH2 increased with the length of the repeat sequence. Furthermore, MSH2 bound preferentially to looped-out CAG repeat sequences, implicating a strand asymmetry in MSH2 recognition. Our results are consistent with the idea that MSH2 may participate in trinucleotide repeat expansion via its role in repair and/or recombination.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding, Competitive
  • DNA / chemistry
  • DNA / metabolism
  • DNA Repair
  • DNA-Binding Proteins*
  • Humans
  • MutS Homolog 2 Protein
  • Nerve Degeneration / genetics*
  • Nucleic Acid Heteroduplexes
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism*
  • Substrate Specificity
  • Trinucleotide Repeats*


  • DNA-Binding Proteins
  • Nucleic Acid Heteroduplexes
  • Proto-Oncogene Proteins
  • DNA
  • MSH2 protein, human
  • MutS Homolog 2 Protein